Downloaded from jmg.bmj.com on August 4, 2011 - Published by group.bmj.com Review Hirschsprung disease, associated syndromes and genetics: a review J Amiel,1 E Sproat-Emison,2 M Garcia-Barcelo,3 F Lantieri,4,5 G Burzynski,6 S Borrego,7 A Pelet,1 S Arnold,2 X Miao,3 P Griseri,4 A S Brooks,6,8 G Antinolo,7 L de Pontual,1 M Clement-Ziza,1 A Munnich,1 C Kashuk,2 K West,2 K K-Y Wong,3 S Lyonnet,1 A Chakravarti,2 P K-H Tam,3 I Ceccherini,4 R M W Hofstra,6 R Fernandez,7 for the Hirschsprung Disease Consortium ABSTRACT HSCR appears an excellent model to study 1 Universite´Paris 5-Descartes, Hirschsprung disease (HSCR, aganglionic megacolon) common multifactorial diseases. The major sus- Faculte´ de Me´decine; INSERM represents the main genetic cause of functional intestinal ceptibility gene is RET, which is also involved in U-781; AP-HP, Hoˆpital Necker- obstruction with an incidence of 1/5000 live births. This multiple endocrine neoplasia type 2 (MEN 2) and Enfant Malades, Paris, France; 2 McKusick-Nathans Institute of developmental disorder is a neurocristopathy and is familial medullary thyroid carcinoma (FMTC). Genetic Medicine, Johns characterised by the absence of the enteric ganglia along Coding sequence mutations are identified in about Hopkins University School of a variable length of the intestine. In the last decades, the 50% and 15% of familial and sporadic HSCR cases, Medicine, Baltimore, USA; development of surgical approaches has importantly respectively. The far most frequent HSCR predis- 3 Division of Paediatric Surgery, Department of Surgery, Li Ka decreased mortality and morbidity which allowed the posing event at the RET locus is a haplotype which Shing Faculty of Medicine of the emergence of familial cases. Isolated HSCR appears to be comprises an SNP lying in an enhancer element of University of Hong Kong, Hong a non-Mendelian malformation with low, sex-dependent RET intron 1. The identification of modifier genes 4 Kong SAR, China; Laboratorio penetrance, and variable expression according to the is currently underway by using various approaches di Genetica Molecolare, Istituto length of the aganglionic segment. While all Mendelian G. Gaslini, L.go G. Gaslini 5, Italy; and an international consortium has been settled 5 Dipartimento di Scienze della modes of inheritance have been described in syndromic in 2004 in order to achieve this goal. Salute, Sezione Biostatistica, HSCR, isolated HSCR stands as a model for genetic HSCR occurs as an isolated trait in 70% of Universita`degli Studi di Genova, disorders with complex patterns of inheritance. The 6 patients, is associated with a chromosomal Genova, Italy; Department of tyrosine kinase receptor RET is the major gene with both Genetics, University Medical abnormality in 12% of the cases, and with Center Groningen, University of rare coding sequence mutations and/or a frequent variant additional congenital anomalies in 18% of the Groningen, Groningen, The located in an enhancer element predisposing to the cases.10–15 In the latter group of patients, some 7 Netherlands; Unidad Clinica de disease. Hitherto, 10 genes and five loci have been found monogenic syndromes can be recognised. Indeed, Genetica y Reproduccion. to be involved in HSCR development. thus far, genetic heterogeneity in HSCR has been Hospitales Universitarios Virgen del Rocio and Centro de demonstrated with 10 specific genes involved. The Investigacio´n Biome´dica en Red aim of this paper is to update a 6 year old review de Enfermedades Raras Harald Hirschsprung, a Danish paediatrician, first on clinical and molecular data about isolated and (CIBERER), Sevilla, Spain; described in 1888 two unrelated boys who died 8 syndromic HSCR. Department of Clinical from chronic severe constipation with abdominal Genetics, Erasmus MC, 1 Rotterdam, The Netherlands distension resulting in congenital megacolon. The absence of intramural ganglion cells of the myen- DEFINITION AND CLASSIFICATION Correspondence to: teric and submucosal plexuses (Auerbach and HSCR is a congenital malformation of the hindgut Dr Jeanne Amiel, INSERM U781 Meissner plexuses, respectively) downstream of characterised by the absence of parasympathetic et De´partement de Ge´ne´tique, the dilated part of the colon was recognised as the intrinsic ganglion cells in the submucosal and Hoˆpital Necker-Enfants Malades, 2 149, rue de Se`vres 75743 Paris cause of the disease in the 1940s.2 This allowed a myenteric plexuses. It is regarded as the conse- Cedex 15, France; amiel@ simple and reliable diagnostic confirmation from quence of the premature arrest of the craniocaudal necker.fr rectal suction biopsies using histochemical staining migration of vagal neural crest cells in the hindgut for acetylcholinesterase (AchE).3 In 1948, Swenson between the fifth and 12th week of gestation to Received 21 August 2007 and Bill developed a surgical procedure4 and the form the enteric nervous system (ENS) and is Revised 21 August 2007 6 16 Accepted 27 August 2007 survival of patients uncovered familial transmis- therefore regarded as a neurocristopathy. While Published Online First sion of Hirschsprung disease (HSCR).5 In 1974, the internal anal sphincter is the constant inferior 26 October 2007 Bolande proposed the term neurocristopathy for limit, patients could be classified as short-segment syndromes or tumours involving the neural crest HSCR (S-HSCR: 80% of cases) when the aganglio- (NC) cells.6 HSCR resulting from an anomaly of nic segment does not extend beyond the upper the enteric nervous system (ENS) of NC origin is sigmoid, and long-segment HSCR (L-HSCR: 20% therefore regarded as a neurocristopathy.6–8 of cases) when aganglionosis extends proximal to Isolated HSCR appears to be of complex, non- the sigmoid. Four HSCR variants have been Mendelian inheritance with low, sex-dependent reported: (1) total colonic aganglionosis (TCA, 3– penetrance, variable expression according to the 8% of cases)17; (2) total intestinal HSCR when the length of the aganglionic segment and suggestive whole bowel is involved17; (3) ultra-short segment of the involvement of one or more gene(s) with HSCR involving the distal rectum below the pelvic low penetrance.59These parameters must be taken floor and the anus18; (4) suspended HSCR, a into account for accurate evaluation of recurrence controversial condition, where a portion of the risk in relatives. With a relative risk as high as 200, colon is aganglionic above a normal distal segment. J Med Genet 2008;45:1–14. doi:10.1136/jmg.2007.053959 1 Downloaded from jmg.bmj.com on August 4, 2011 - Published by group.bmj.com Review CLINICAL FEATURES AND DIAGNOSIS soiling.31 32 Mortality has been below 6% since the 1980s and In most cases, the diagnosis of HSCR is made in the newborn may be related to short term complications or caused by the period15 due to intestinal obstruction with the following associated malformations.31 However, the treatment of children features: (1) delayed of passage of meconium (.24 h after with TCA remains hazardous.33 34 birth); (2) abdominal distension that is relieved by rectal stimulation or enemas; (3) vomiting; and (4) neonatal entero- EPIDEMIOLOGY colitis. Some patients are diagnosed later in infancy or in The incidence of HSCR is estimated at 1/5000 live births.5 adulthood with severe constipation, chronic abdominal disten- However, the incidence varies significantly among ethnic sion, vomiting, and failure to thrive.19 Finally, although a rare groups (1.0, 1.5, 2.1, and 2.8 per 10 000 live births in presentation, unexplained perforation of the caecum or appen- Hispanics, Caucasian-Americans, African-Americans, and dix should make the diagnosis considered. Asians, respectively).15 S-HSCR is far more frequent than On abdominal x ray a distended small bowel and proximal L-HSCR (80% and 20%, respectively).10 12 There is a sex bias colon, with absence of rectal gas, are common findings. The with a preponderance of affected males and a sex ratio of 4/1.35 classical image is a dilated proximal colon with the aganglionic Interestingly, the male:female ratio is significantly higher for cone narrowing towards the distal gut. On barium enema a S-HSCR (4.2–4.4) than for L-HSCR (1.2–1.9) (table 1).15 35 small rectum with uncoordinated contractions is seen. The transitional zone represents the site where the narrow aganglionic bowel joins the dilated ganglionic bowel. On a MOLECULAR GENETICS IN ISOLATED HSCR delayed plain x ray taken 24 h after the enema, barium retention Several genes have been implicated in isolated HSCR, the two is observed. Anorectal manometry shows absence of relaxation major ones being RET and EDNRB. of the internal sphincter (rectal inhibitory reflex) in response to rectal distension.20 The reliability of this test becomes excellent The RET signalling pathway from day 12 after birth where the normal rectoenteric reflex is The first susceptibility locus was mapped to 10q11.2 in present.21 Suction rectal biopsy remains the gold standard for multigenerational families segregating HSCR as an incompletely confirming the diagnosis in most cases demonstrating an penetrant autosomal dominant trait.36 37 This region had been increased acetyl cholinesterase activity.22 Nonetheless, full targeted because of the observation of an interstitial deletion of thickness rectal biopsy is the golden standard in reaching the chromosome 10q11 in patients with TCA and mental retarda- diagnosis. Furthermore, seromuscular biopsies will be needed at tion.38 The proto-oncogene RET (REarranged during operation to define the proximal limit of the aganglionic Transfection), identified as disease causing in MEN 239 40 and segment. mapping in 10q11.2, was regarded as a candidate gene owing to: (1) co-occurrence of MEN 2A and HSCR in some families; and DIFFERENTIAL DIAGNOSES (2) expression in neural-crest derived cells.